A subject of the present Application is new derivatives of 2-arylimino-2,3-dihydrothiazoles and their preparation processes. These products have a good affinity with certain sub-types of somatostatin receptors and therefore have useful pharmacological properties. The invention also relates to these same products as medicaments, the pharmaceutical compositions containing them and their use for the preparation of a medicament intended to treat pathological states or diseases in which one (or more) somatostatin receptors are involved.
Somatostatin (SST) is a cyclic tetradecapeptide which was isolated for the first time from the hypothalamus as a substance which inhibits the growth hormone (Brazeau P. et al., Science 1973, 179, 77-79). It also operates as a neurotransmitter in the brain (Reisine T. et al., Neuroscience 1995, 67, 777-790; Reisine T. et al., Endocrinology 1995, 16, 427-442). Molecular cloning has allowed it to be shown that the bioactivity of somatostatin depends directly on a family of five receptors linked to the membrane.
The heterogeneity of the biological functions of somatostatin has lead to studies which try to identify the structure-activity relationships of peptide analogues on somatostatin receptors, which has led to the discovery of 5 sub-types of receptors (Yamada et al., Proc. Natl. Acad. Sci. U.S.A, 89, 251-255, 1992; Raynor, K. et al, Mol. Pharmacol., 44, 385-392, 1993). The functional roles of these receptors are currently being actively studied. The affinities with different sub-types of somatostatin receptors have been associated with the treatment of the following disorders/diseases. Activation of sub-types 2 and 5 has been associated with suppression of the growth hormone (GH) and more particularly with that of adenomas secreting GH (acromegalia) and those secreting hormone TSH. Activation of sub-type 2 but not sub-type 5 has been associated with the treatment of adenomas secreting prolactin. Other indications associated with the activation of sub-types of somatostatin receptors are the recurrence of stenosis, inhibition of the secretion of insulin and/or of glucagon and in particular diabetes mellitus, hyperlipidemia, insensiblity to insulin, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and nephropathy; inhibition of the secretion of gastric acid and in particular peptic ulcers, enterocutaneous and pancreaticocutaneous fistulae, irritable colon syndrome, dumping syndrome, aqueous diarrhea syndrome, diarrhea associated with AIDS, diarrhea induced by chemotherapy, acute or chronic pancreatitis and secretory gastrointestinal tumors; the treatment of cancer such as hepatomas; the inhibition of angiogenesis, the treatment of inflammatory disorders such as arthritis; chronic rejection of allografts; angioplasty; the prevention of bleeding of grafted vessels and gastrointestinal bleeding. The agonists of somatostatin can also be used to reduce the weight of a patient.
Among the pathological disorders associated with somatostatin (Moreau J. P. et al., Life Sciences 1987, 40, 419; Harris A. G. et al., The European Journal of Medicine, 1993, 2, 97-105), there can be mentioned for example: acromegalia, hypophyseal adenomas, Cushing""s disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumors including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison""s syndrome, GRFoma as well as acute bleeding of the esophageal varices, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrheas, refractory diarrheas of acquired immunodeficiency syndrome, chronic secretary diarrhea, diarrhea associated with irritable bowel syndrome, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as hemorrhages of the varices in patients with cirrhosis, gastro-intestinal hemorrhage, hemorrhage of the gastroduodenal ulcer, Crohn""s disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and other therapeutic fields such as, for example, cephaleas including cephalea associated with hypophyseal tumors, pain, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan""s syndrome, sleep apnea syndrome, Graves"" disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, as well as Alzheimer""s disease. Osteoporisis can also be mentioned. The Applicant found that the compounds of general formula (I) described hereafter have an affinity and a selectivity for the somatostatin receptors. As somatostatin and its peptide analogues often have a poor bioavailability by oral route and a low selectivity (Robinson, C., Drugs of the Future, 1994, 19, 992; Reubi, J. C. et al., TIPS, 1995, 16, 110), said compounds, non-peptide agonists or antagonists of somatostatin, can be advantageously used to treat pathological states or illnesses as presented above and in which one (or more) somatostatin receptors are involved. Preferably, said compounds can be used for the treatment of acromegalia, hypophyseal adenomas or endocrine gastroenteropancreatic tumors including carcinoid syndrome.
The compounds of the present invention correspond to general formula (I) 
in racemic, enantiomeric form or all combinations of these forms, in which:
R1 represents an amino(C2-C7)alkyl, aminoalkylarylalkyl, aminoalkylcycloalkylalkyl, (C1-C15)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl(C3-C6)cycloalkyl, (C3-C6)cycloalkylalkyl, cyclohexenylalkyl, alkenyl, alkynyl, carbocyclic aryl radical containing at least two rings of which at least one is not aromatic, carbocyclic or heterocyclic aralkyl radical optionally substituted on the aryl group, bis-arylalkyl, alkoxyalkyl, furannylalkyl, tetrahydrofurannylalkyl, dialkylaminoalkyl, N-acetamidoalkyl, cyanoalkyl, alkylthioalkyl, arylhydroxyalkyl, aralkoxyalkyl, morpholinoalkyl, pyrrolidinoalkyl, piperidinoalkyl, N-alkylpyrrolidinoalkyl, N-alkylpiperazinylalkyl or oxopyrrolidinoalkyl radical,
or R1 represents one of the radicals represented below: 
or also R1 represents a xe2x80x94C(R11)(R12)xe2x80x94COxe2x80x94R10 radical;
R2 represents an optionally substituted carbocyclic or heterocyclic aryl radical,
R2 represents one of the radicals represented below: 
R3 represents an alkyl, adamantyl, optionally substituted carbocyclic or heterocyclic aryl radical, carbocyclic or heterocyclic aralkyl optionally substituted on the aryl group,
or R3 represents one of the radicals represented below: 
or also R3 represents a xe2x80x94COxe2x80x94R5 radical;
R4 represents H, alkyl, carbocyclic or heterocyclic aralkyl optionally situated on the aryl radical;
or then the 
xe2x80x83radical represents a radical of general formula 
in which i represents an integer from 1 to 3;
R5 represents the N(R6)(R7) radical;
R6 represents a (C1-C16)alkyl, cycloalkylalkyl, hydroxyalkyl, aryloxyalkyl radical, carbocyclic or heterocyclic aralkyl radical optionally substituted on the aryl group, aralkoxyalkykl, arylhydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, cyclohexenyl, cyclohexenylalkyl, alkylthiohydroxyalkyl, cyanoalkyl, N-acetamidoalkyl radical, bis-arylalkyl radical optionally substituted on the aryl groups, di-arylalkyl radical optionally substituted on the aryl groups, morpholinoalkyl, pyrrolidinoalkyl, piperidinoalkyl, N-alkylpyrrolidinoalkyl, oxopyrrolidinoalkyl, tetrahydrofurannylalkyl, N-benzylpyrrolidinoalkyl, N-alkylpiperazinylalkyl, N-benzylpiperazinylalkyl, N-benzylpiperidinylalkyl or N-alkoxycarbonylpiperidinyl radical, or R6 represents a (C3-C8)cycloalkyl radical optionally substituted by a radical chosen, from the group comprising the hydroxy radical and an alkyl radical,
or R6 represents one of the radicals represented below: 
R7 represents H or an alkyl, hydroxyalkyl, mono- or di-aminoalkyl or aralkyl radical;
or the xe2x80x94N(R6)(R7) radical represents the radical of the following general formula: 
xe2x80x83in which:
R8 represents H, alkyl, hydroxyalkyl, optionally substituted carbocyclic or heterocyclic aryl, aralkyl optionally substituted on the aryl group, alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, bis-arylalkyl, piperidinyl, pyrrolidinyl, hydroxy, arylalkenyl,
or R8 represents xe2x80x94Xxe2x80x94(CH2)bxe2x80x94R9;
R9 represents H or an alkyl, alkoxy, aryloxy, optionally substituted carbocyclic or heterocyclic aryl, morpholinyl, pyrrolidinyl, alkylamino or N,Nxe2x80x2-(alkyl)(aryl)amino radical;
X represents CO, COxe2x80x94NH or SO2; 
Y represents CH or N;
a represents 1 or 2;
b represents an integer from 0 to 6;
or the N(R6)(R7) radical represents a radical of general formula 
xe2x80x83in which:
Z represents CH, O or S;
c represents an integer from 0 to 4;
or the N(R6)(R7) radical represents one of the radicals represented below: 
R10 represents an amino(C2-C7)alkylamino, ((aminoalkyl)aryl)alkylamino, ((aminoalkyl)cycloalkyl)alkylamino, piperazinyl, homopiperazinyl radical, or R10 represents the radical represented below: 
R11 represents H;
R12 represents H or an alkyl, (C3-C7)cycloalkyl, optionally substituted carbocyclic or heterocyclic aralkyl, propargyl, allyl, hydroxyalkyl, alkylthioalkyl, arylalkylalkoxyalkyl, arylalkylthioalkoxyalkyl radical;
or the compounds of the invention are salts of the compounds of general formula (I).
When the compounds of general formula (I) contain the R1, R2, R3, R4, R6, R8 or R9 radicals including an substituted aryl radical or an aralkyl substituted on the aryl group, said aryl or aralkyl radicals are preferably such that:
For R1, when the aryl group is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule) by the radicals chosen independently from the group comprising a halogen atom and an alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryl, aralkoxy or SO2NH2 radical. Two substituents can, if appropriate, be linked together and form a ring, for example by representing together a methylenedioxy or propylene radical.
For R2, when the aryl group is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule) by the radicals chosen independently from the group comprising a halogen atom and an alkyl, alkoxy, alkylthio, haloalkyl, alkenyl, haloalkoxy, nitro, cyano, azido, SO2N, mono- or di-alkylamino, aminoalkyl, aralkoxy or aryl radical. Two substituents can, if appropriate, be linked together and form a ring, for example by representing together a methylenedioxy, ethylenedioxy or propylene radical.
For R3, when the aryl group or groups (originating from an aryl or aralkyl radical) are substituted, they can be, according to the case, from 1 to 5 times (other than the bond which links them with the remainder of the molecule). The carbocyclic aryl or aralkyl radicals can be substituted from 1 to 5 times on the aryl ring by the radicals chosen independently from the group comprising a halogen atom and an alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, azido, mono- or di-alkylamino, pyrrolidinyl, morpholinyl, aralkoxy or aryl radical. Two substituents can, if appropriate, be linked together and form a ring, for example by representing together an alkylenedioxy radical containing 1 to 3 carbon atoms. The heterocyclic aryl or aralkyl radicals of R3 can be substituted 1 to 2 times on the ring by the radicals chosen independently from the group comprising a halogen atom and an alkyl radical.
For R4, when the aryl group is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule). The aryl radical can be substituted by the radicals chosen independently from the group comprising a halogen atom and an alkyl or alkoxy radical.
For R6, when the aryl group or groups are substituted, they can be from 1 to 5 times (other than the bond which links them with the remainder of the molecule). The optional substituents on the aryl groups are chosen independently from the group comprising a halogen atom and an alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryl, aryloxy or SO2NH2 radical.
For R8, when the aryl group or groups are substituted, they can be from 1 to 5 times (other than the bond which links them with the remainder of the molecule). The optional substituents on the aryl groups are chosen independently from the group comprising a halogen atom and an alkyl, haloalkyl, alkoxy, hydroxy, cyano, nitro or alkylthio radical.
For R9, when the carbocyclic or heterocyclic aryl radical is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule). The optional substituents on the aryl group are chosen independently from the group comprising a halogen atom and an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, carbocyclic aryl, hydroxy, cyano or nitro radical.
For R12, when the carbocyclic or heterocyclic aryl radical is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule). The optional substituents on the aryl group are chosen independently from the group comprising a halogen atom and an alkyl, alkoxy, carbocyclic aryl, aralkoxy, hydroxy, cyano or nitro radical.
By alkyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms. By cycloalkyl, unless specified otherwise, is meant a monocyclic carbon system containing 3 to 7 carbon atoms. By alkenyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond). By alkynyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one double unsaturation (triple bond). By carbocyclic or heterocyclic aryl, is meant a carbocyclic or heterocyclic system containing at least one aromatic ring, a system referred to as heterocyclic when at least one of the rings which comprise it contains a heteroatom (O, N or S). By haloalkyl, is meant an alkyl radical of which at least one of the hydrogen atoms (and optionally all) is replaced by a halogen atom.
By alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl and aralkyl radicals, is meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl and aralkyl radicals the alkyl radical of which has the meaning indicated previously.
By linear or branched alkyl having 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By cycloalkyl, is meant in particular the cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexyl and cycloheptanyl radicals. By carbocyclic or heterocyclic aryl, is meant in particular the phenyl, naphthyl, pyridinyl, furannyl, thiophenyl, indanyl, indolyl, imidazolyl, benzofurannyl, benzothiophenyl, phthalimidyl radicals. By carbocyclic or heterocyclic aralkyl, is meant in particular the benzyl, phenylethyl, phenylpropyl, phenylbutyl, indolylalkyl, phthalimidoalkyl, naphthylalkyl, furannylalkyl, thiophenylalkyl, benzothiophenylalkyl, pyridinylalkyl and imidazolylalkyl radicals.
When an arrow emanates from a chemical structure, said arrow indicates the attachment point. For example: 
represents the benzyl radical.
Preferably, the compounds of general formula (I) are such that:
R1 represents xe2x80x94C(R11)(R12)xe2x80x94COxe2x80x94R10 or one of the following radicals: 
R2 represents one of the following radicals: 
R3 represents COxe2x80x94R5 or one of the following radicals: 
R4 represents H, alkyl, carbocyclic or heterocyclic aralkyl optionally substituted on the aryl radical;
or then the 
xe2x80x83radical represents a radical of general formula 
xe2x80x83in which i represents an integer from 1 to 3;
R5 represents one of the following radicals: 
R10 represents one of the following radicals: 
R11 represents H;
R12 represents one of the following radicals: 
it being understood that for R4, when the aryl group is substituted, it can be from 1 to 5 times (other than the bond which links it with the remainder of the molecule) by the radicals chosen independently from the group comprising a halogen atom and an alkyl or alkoxy radical.
The compounds of the invention are preferably such that R4 represents H.
More preferentially, the compounds according to the invention correspond to general formula (II) 
in which:
either R1 represents one of the radicals below 
R2 represents one of the radicals below 
R3 represents one of the radicals below 
and R4 represents H;
or also R1 represents one of the radicals below 
R2 represents one of the radicals below 
R3 represents COR5,
R4 represents H,
and R5 represents one of the radicals below 
or finally R1 represents the xe2x80x94C(R11)(R12)xe2x80x94COxe2x80x94R10 radical in which
R10 represents the radical 
R11 represents H
and R12 represents the radical 
R2 represents the radical 
R3 represents the radical 
and R4 represents H.
Moreover, the invention relates to preparation processes on a solid support for the compounds of general formula (I) described previously (also applicable to the corresponding compounds of general formula (II)).
According to the invention, the compounds of general formula (I)a 
in which:
R1 represents a xe2x80x94CH2xe2x80x94Alxe2x80x94NH2 radical, in which Al represents a xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)pxe2x80x94, aralkylene or cycloalkylalkylene radical, n and p represent integers from 1 to 6;
R2 and R4 represent the same radicals as in general formula (I);
and R3 represents the same radicals as in general formula (I), with the exception of the xe2x80x94COxe2x80x94R5 radicals;
can be prepared for example according to a process characterized in that it comprises the following successive stages:
1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a p-nitrophenylcarbonate Wang resin with a large excess of R1xe2x80x94NH2 symmetrical diamine;
2) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of the resin isolated after stage 1) with an aromatic isothiocyanate of general formula R2xe2x80x94Nxe2x95x90Cxe2x95x90S in which the R2 radical has the same meaning as in general formula (I)a;
3) treatment, in an aprotic solvent such as dioxane or dimethylformamide, of the resin obtained in Stage 2) with the compound of general formula (III) 
xe2x80x83in which the R3 and R4 radicals have the same meaning as in general formula (I)a;
4) cleavage of the resin under acid conditions;
5) treatment under basic conditions of the product obtained after Stage 4).
The preparation of the p-nitrophenylcarbonate Wang resin is described further on in the part entitled xe2x80x9cPREPARATION OF THE COMPOUNDS OF THE INVENTIONxe2x80x9d.
Preferably, for the above process, in order to have the large excess in Stage 1), of the order of 10 to 20 equivalents of diamine R1xe2x80x94NH2 will be used. Stage 1) is preferably carried out at ambient temperature. Stage 3) is carried out at a temperature greater than ambient temperature, for example at a temperature comprised between 60 and 90xc2x0 C., using of the order of 2 to 5 equivalents of the compound of general formula (III). In Stage 4), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 5), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
According to a variant of the invention, the compounds of general formula (I)b 
in which:
R1 represents the same radicals as in general formula (I), with the exception of the xe2x80x94CH2xe2x80x94Alxe2x80x94NH2 type radicals, in which Al represents a xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)pxe2x80x94, aralkylene or cycloalkylalkylene radical, n and p representing integers from 1 to 6, and also with the exception of the xe2x80x94C(R11)(R12)xe2x80x94COxe2x80x94R10 radicals;
R2 represents an aminoalkylphenyl radical;
R3 represents the same radicals as in general formula (I), with the exception of the xe2x80x94COxe2x80x94R5 radicals;
and R4 represents the same radicals as in general formula (I);
can be prepared for example according to a process characterized in that it comprises the following successive stages:
1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a p-nitrophenylcarbonate Wang resin with an excess of aminoalkylaniline of general formula R2xe2x80x94NH2 in which the R2 radical has the same meaning as in general formula (I)b;
2) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of the resin isolated after Stage 1) with an isothiocyanate of general formula R1xe2x80x94Nxe2x95x90Cxe2x95x90S in which the R1 radical has the same meaning as in general formula (I)b;
3) treatment, in an aprotic solvent such as dioxane or dimethylformamide, of the resin obtained in Stage 2) with the compound of general formula (III) 
xe2x80x83in which the R3 and R4 radicals have the same meaning as in general formula (I)b;
4) cleavage of the resin under acid conditions;
5) treatment under basic conditions of the product obtained after Stage 4).
Preferably, for the above process, in order to have the excess in Stage 1), of the order of 5 to 10 equivalents of aminoalkylaniline will be used. Stage 1) is preferably carried out at ambient temperature. Stage 3) is carried out at a temperature greater than ambient temperature, for example at a temperature comprised between 60 and 90xc2x0 C., using of the order of 2 to 5 equivalents of the compound of general formula (III). In Stage 4), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 5), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
According to another variant of the invention, the compounds of general formula (I)c 
in which:
R1 represents a xe2x80x94CH2xe2x80x94Alxe2x80x94NH2 radical, in which Al represents a xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)pxe2x80x94, aralkylene or cycloalkylalkylene radical, n and p representing integers from 1 to 6;
R2 represents the same radicals as in general formula (I);
R3 represents a xe2x80x94COxe2x80x94R5 radical; and R4 and R5 represent the same radicals as in general formula (I);
can be prepared according to a process characterized in that it comprises the following successive stages:
1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a p-nitrophenylcarbonate Wang resin with a large excess of symmetrical diamine of formula R1xe2x80x94NH2 in which the R1 radical has the same meaning as in general formula (I)c;
2) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of the resin isolated after Stage 1) with an aromatic isothiocyanate of formula R2xe2x80x94Nxe2x95x90Cxe2x95x90S in which the R2 radical has the same meaning as in general formula (I)c;
3) treatment, in an aprotic solvent such as dioxane or dimethylformamide, of the resin obtained in Stage 2) with the acid of general formula (IV) 
xe2x80x83in which the R4 radical has the same meaning as in the general formula (I)c;
4) peptide coupling;
5) cleavage of the resin under acid conditions;
6) treatment under basic conditions of the product obtained after Stage 5).
Preferably, for the above process, in order to have the large excess in Stage 1) of the order of 10 to 20 equivalents of symmetrical diamine will be used. Stage 1) is preferably carried out at ambient temperature. Stage 3) is carried out at a temperature greater than ambient temperature, for example at a temperature comprised between 60 and 90xc2x0 C., using of the order of 2 to 5 equivalents of the acid of general formula (IV). The peptide coupling of Stage 4) is carried out for example in DMF with coupling agents such as for example dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1.1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1.1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and aminated compounds. Preferably, the coupling agents are used in proportions of 4 to 5 equivalents, as with the aminated compounds, and the reaction will take place at a temperature of the order of ambient temperature for a duration of the order of 1 to 24 hours. In Stage 5), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 6), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
According to yet another variant, the compounds of general formula (I)d 
in which:
R1 represents the same radicals as in general formula (I) as defined in claim 1, with the exception of the xe2x80x94CH2xe2x80x94Alxe2x80x94NH2 type radicals, in which Al represents a xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)pxe2x80x94, aralkylene or cycloalkylalkylene radical, n and p represent integers from 1 to 6, and also with the exception of the xe2x80x94C(R11)(R12)xe2x80x94COxe2x80x94R10 radicals;
R2 represents an aminoalkylphenyl radical;
R3 represents a xe2x80x94COxe2x80x94R5 radical;
and R4 and R5 represent the same radicals as in general formula (I);
can be prepared according to a process characterized in that it comprises the following successive stages:
1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a p-nitrophenylcarbonate Wang resin with an excess of aminoalkylaniline of general formula R2xe2x80x94NH2 in which the R2 radical has the same meaning as in general formula (I)d;
2) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of the resin isolated after Stage 1) with an isothiocyanate of general formula R1xe2x80x94Nxe2x95x90Cxe2x95x90S in which the R1 radical has the same meaning as in general formula (I)d;
3) treatment, in an aprotic solvent such as dioxane or dimethylformamide, of the resin obtained in Stage 2) with the acid of general formula (IV) 
xe2x80x83in which the R4 radical has the same meaning as in general formula (I)d;
4) peptide coupling;
5) cleavage of the resin under acid conditions;
6) treatment under basic conditions of the product obtained after Stage 5).
Preferably, for the above process, in order to have the excess in Stage 1), of the order of 5 to 10 equivalents of aminoalkylaniline will be used. Stage 1) is preferably carried out at ambient temperature. Stage 3) is carried out at a temperature greater than ambient temperature, for example at a temperature comprised between 60 and 90xc2x0 C., using of the order of 2 to 5 equivalents of the acid of general formula (IV). The peptide coupling of Stage 4) is carried out for example in DMF with coupling agents such as for example dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and aminated compounds. Preferably, the coupling agents are used in proportions of 4 to 5 equivalents, as with the aminated compounds, and the reaction will take place at a temperature of the order of ambient temperature for a duration of the order of 1 to 24 hours. In Stage 5), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 6), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
According to another variant, the compounds of general formula (I)e 
in which:
R1 represents the same radicals as in general formula (I), with the exception of the xe2x80x94CH2xe2x80x94Al xe2x80x94NH2 radicals, in which Al represents a xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)pxe2x80x94, aralkylene or cycloalkylalkylene radical, n and p representing integers from 1 to 6, and also with the exception of the xe2x80x94C(R11)(R12)xe2x80x94COxe2x80x94R10 radicals;
R2 represents the same radicals as in general formula (I);
R3 represents a xe2x80x94COxe2x80x94R5 radical;
R4 represents H;
R5 represents a xe2x80x94CH2xe2x80x94Alxe2x80x94NH2 radical, in which Al represents a linear or branched alkylene radical containing 1 to 6 carbon atoms, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)pxe2x80x94, aralkylene or cycloalkylalkylene, n and p representing integers from 1 to 6, or also R5 represents the N(R6)(R7) radical corresponding to the following general formula: 
xe2x80x83in which:
R8 represents H;
Y represents N;
a represents 1 or 2;
can be prepared by a process characterized in that it comprises the following successive stages:
1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a p-nitrophenylcarbonate Wang resin with a large excess of symmetrical diamine of general formula R5xe2x80x94H;
2) peptide coupling with the acid of general formula (IV) on the resin obtained in Stage 1) 
xe2x80x83in which the R4 radical has the same meaning as that in the general formula (I)e;
3) reaction of the primary amine of general formula R1xe2x80x94NH2 with the isothiocyanate of general formula R2xe2x80x94NCS in a solvent such as dimethylformamide or dioxane, R1 and R2 having the same meanings as in general formula (I)e;
4) addition of the thiourea obtained in Stage 3) to the resin obtained in Stage 2) and heating the mixture;
5) cleavage of the resin under acid conditions;
6) treatment under basic conditions of the product obtained after Stage 5).
Preferably, for the above process, in order to have the large excess in Stage 1), of the order of 10 to 20 equivalents of diamine R5xe2x80x94NH2 will be used. Stage 1) is preferably carried out at ambient temperature. The peptide coupling of Stage 2) is carried out in DMF with a coupling agent such as for example a DIC/N-hydroxybenzotriazole (HOBt) mixture. Preferably, the reaction of Stage 3) is carried out in a solvent such as dimethylformamide or dioxane. During the addition of Stage 4), 2 to 5 equivalents of thiourea will be used per equivalent of resin; preferably, heating will be carried out at a at a temperature greater than ambient temperature, for example at a temperature from 40 to 100xc2x0 C. (in particular at a temperature of approximately 80xc2x0 C.) and for a duration of the order of 2 to 24 hours. In Stage 5), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 6), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
According to yet another variant, the compounds of general formula (I)f 
in which:
R1 represents a xe2x80x94C(R11R12)xe2x80x94COxe2x80x94R10 radical;
R2, R3 and R4 represent the same radicals as in general formula (I);
R10 represents an amino(C2-C7)alkylamino, ((aminoalkyl)aryl)alkylamino, ((aminoalkyl)cycloalkyl)alkylamino, piperazinyl, homopiperazinyl radical,
or R10 represents the radical represented below: 
R11 represents H;
R12 represents H or an alkyl, (C3-C7)cycloalkyl, optionally substituted carbocyclic or heterocyclic aralkyl, propargyl, allyl, hydroxyalkyl, alkylthioalkyl, arylalkylalkoxyalkyl, arylalkylthioalkoxyalkyl radical;
can be prepared by a process characterized in that it comprises the following successive stages:
1) treatment, in an aprotic solvent such as dichloromethane or dimethylformamide, of a p-nitrophenylcarbonate Wang resin with a large excess of symmetrical diamine of general formula R10xe2x80x94H in which R10 has the same meaning as in general formula (I)f;
2) peptide coupling of the resin obtained in Stage 1) with an amino acid of general formula HOOCxe2x80x94C(R11)(R12)xe2x80x94NHxe2x80x94Fmoc in which R11 and R12 have the same meaning as in general formula (I)f;
3) cleavage of the Fmoc group of the resin obtained in Stage 2);
4) reaction of the resin obtained in Stage 3) with an isothiocyanate of general formula R2xe2x80x94NCS in which R2 has the same meaning as in general formula (I)f;
5) cleavage of the resin under acid conditions;
6) treatment under basic conditions of the product obtained after Stage 5).
Preferably, for the above process, in order to have the large excess in Stage 1), of the order of 10 to 20 equivalents of diamine R10xe2x80x94H will be used. Stage 1) is preferably carried out at ambient temperature. The peptide coupling of Stage 2) is carried out for example in DMF with coupling agents such as for example dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). Preferably, the reaction of Stage 2) is carried out at ambient temperature and for a duration of 1 to 24 hours. The deprotection of Stage 3) can be carried out, for example, by means of a mixture of DMF containing 20% piperidine. Stage 4) will preferably be carried out in a solvent such as dimethylformamide or dichloromethane, the isothiocyanate preferably being added in a proportion of 5 to 10 equivalents per equivalent of the resin obtained in Stage 3). In Stage 5), the acid conditions can for example be created by using a dichloromethane/trifluoroacetic acid mixture at 50%, said acid conditions being preferably maintained for a duration of the order of 1 to 2 hours. In Stage 6), the basic conditions can for example be created by using a saturated solution of sodium hydrogen carbonate or by elution on a basic alumina cartridge.
A subject of the invention is also, as medicaments, the compounds of general formulae (I) and (II) described previously or their pharmaceutically acceptable salts. It also relates to the pharmaceutical compositions containing said compounds or their pharmaceutically acceptable salts, and their use for the preparation of a medicament intended to treat the pathological states or the diseases in which one (or more) of the somatostatin receptors are involved.
In particular, the compounds of general formulae (I) and (II) described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological states or the diseases chosen from the group comprising the following pathological states or diseases: acromegalia, hypophyseal adenomas, Cushing""s disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, syndrome X, dawn phenomena, angiopathy, angioplasty, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumors including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison""s syndrome, GRFoma as well as acute bleeding of the esophageal varices, ulcers, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrheas, refractory diarrheas of acquired immunodeficiency syndrome, chronic secretary diarrhea, diarrhea associated with irritable bowel syndrome, diarrheas induced by chemotherapy, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as hemorrhages of the varices in patients with cirrhosis, gastro-intestinal hemorrhage, hemorrhage of the gastroduodenal ulcer, bleeding of grafted vessels, Crohn""s disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and in other therapeutic fields such as, for example, cephaleas including cephalea associated with hypophyseal tumors, pain, inflammatory disorders such as arthritis, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, hyperlipidemia, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan""s syndrome, sleep apnea syndrome, Graves"" disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, chronic rejection of allografts as well as Alzheimer""s disease and finally osteoporisis.
Preferably, the compounds of general formulae (I) and (II) described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological states or diseases chosen from the group comprising the following pathological states or diseases: acromegalia, hypophyseal adenomas or endocrinic gastroenteropancreatic tumors including carcinoid syndrome, and gastrointestinal bleeding.
By pharmaceutically acceptable salt is meant in particular addition salts of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide and nitrate, or of organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate, oxalate and stearate. The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to xe2x80x9cPharmaceutical saltsxe2x80x9d, J. Pharm. Sci. 66:1 (1977).
The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax. The suspensions contain in particular suspensions of sustained release microparticles loaded with active ingredient (in particular microparticles of polylactide-co-glycolide or PLGAxe2x80x94cf. for example the Patents U.S. Pat. No. 3,773,919, EP 52 510 or EP 58 481 or the Patent Application PCT WO 98/47489), which allow the administration of a determined daily dose over a period of several days to several weeks.
The pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, as well as their mixtures, in varying proportions, in water.
The administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.
The administration dose envisaged for a medicament according to the invention is comprised between 0.1 mg to 10 g according to the type of active compound used.
These compounds can be prepared according to the methods described below.
First Method
This method is inspired by the protocols described in the following publications: Macholan, L.; Skursky, L. Chem. Listy 1955, 49, 1385-1388; Bestman, H. J.; Seng, F. Chem. Ber. 1963, 96, 465-469; Jones, R. G.; Kornfeld, E. C.; McLaughlin, K. C. J. Am. Chem. Soc. 1950, 72, 4526-4529; Nimgirawath, S.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1973, 26, 183-193). 
A carboxylic acid is firstly converted to an acid by using oxalyl or thionyl chloride, or by activating it in the form of an anhydride using an alkyl chloroformate (for example isobutyl chloroformate, cf. Krantz, A.; Copp, L. J. Biochemistry 1991, 30, 4678-4687; or ethyl chloroformate, cf. Podlech, J.; Seebach, D. Liebigs Ann. 1995, 1217-1228) in the presence of a base (triethylamine or N-methylmorpholine).
The activated carboxyl group is then converted to diazoketone using diazomethane in an ethereal solution or a commercial solution of trimethylsilyldiazomethane (Aoyama, T.; Shiori, T. Chem. Pharm. Bull. 1981, 29, 3249-3255) in an aprotic solvent such as diethyl ether, tetrahydrofuran (THF) or acetonitrile.
The bromination is then carried out using a bromination agent such as hydrobromic acid in acetic acid, aqueous hydrobromic acid in diethyl ether or dichloromethane.
(C12H10BrNO3, MM=296.12): 
Oxalyl chloride (5.8 ml; 66.7 mmol) is added to Pht-xcex2-Ala-OH (9.96 g; 44.5 mmol) dissolved in dichloromethane (120 ml) and 3 drops of dimethylformamide (DMF). The mixture is stirred for 3 hours at ambient temperature. After elimination of the solvent, the white solid is taken up in a 1:1 mixture of anhydrous tetrahydrofuran and acetonitrile (200 ml) then 49 ml of a 2 M solution of (trimethylsilyl) diazomethane in hexane (97.9 mmol) are added dropwise at 0xc2x0 C. The solvents are eliminated after one night of stirring at 0xc2x0 C. The pale yellow solid is then dissolved in dichloromethane (60 ml) and 12 ml of aqueous hydrobromic acid (48%) is added dropwise at 0xc2x0 C. The mixture is stirred until the temperature reaches 15xc2x0 C. and 50 ml of a saturated solution of sodium bicarbonate is added. The organic phase is washed with salt water then dried over sodium sulphate. Crystallization from diethyl ether allows a white solid to be obtained (11.39 g; yield=86%).
NMR 1H (DMSO D6, 100 MHz, xcex4): 7.83 (s, 4H); 4.36 (s, 2H, CH2Br); 3.8 (t, 2H, J=7.1 Hz, NCH2); 2.98 (t, 2H, J=6.9 Hz, CH2CO).
The following compounds were prepared in a similar fashion to the procedure described in Preparation 1:
Second Method
The starting product is an arylmethylketone or a heteroarylmethylketone. 
The starting arylmethylketone or heteroarylmethylketone is converted to the corresponding xcex1-bromoketone by using different brominating agents:
CuBr2 (King, L. C.; Ostrum, G. K. J. Org. Chem. 1964, 29, 3459-3461) heated in ethyl acetate or dioxane;
the N-bromosuccinimide in CCl4 or aqueous acetonitrile,(Morton, H. E.; Leanna, M. R. Tetrahedron Lett. 1993, 34, 4481-4484);
the bromine in glacial acetic acid or sulphuric acid;
phenyltrimethylammonium tribromide (Sanchez, J. P.; Parcell, R. P. J. Heterocyclic Chem, 1988, 25, 469-474) at 20-80xc2x0 C. in an aprotic solvent such as THF or tetrabutylammonium tribromide (Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Fujisaki, S. Bull Chem. Soc. Jpn. 1987, 60, 1159-1160) in a dichloromethane/methanol mixture at ambient temperature;
brominating agent on a polymer support such as perbromide on an Amberlyst A-26 resin, poly(perbromide of vinylpyridinium hydrobromide) (Frechet, J. M. J.; Farrall, M. J. J Macromol. Sci. Chem. 1977, 507-514) in a protic solvent such as methanol at approximately 20-35xc2x0 C. for approximately 2-10 hours.
(C10H7BrO2, MM=239.06): 
A polymer of perbromide of pyridine hydrobromide (8.75 g; 17.5 mmol; 1.4 equivalent) is added to a solution of (benzofuran-2-yl)methylketone (2 g; 12.5 mmol) in methanol (40 ml). The resulting mixture is stirred at ambient temperature for 7 hours and the reaction is stopped by filtration. The methanol is eliminated under reduced pressure and an additional addition of diethyl ether allows crystallization of the expected product (3.6 g; yield=60%).
NMR 1H (DMSO D6, 100 MHz, xcex4): 8.09 (s, 1H); 7.98 (d, 1H, J=6.6 Hz); 7.75 (d, 1H, J=8.4 Hz); 7.58 (t, 1H, J=8.4 Hz); 7.4 (t, 1H, J=7 Hz); 4.83 (s, 2H, CH2Br).
The following compounds have been prepared in similar fashion to the procedure described in Preparation 12:
Preparation of p-nitrophenylcarbonate Wang Resin 
This resin was prepared from Wang resin, acquired from Bachem or Novabiochem with a load greater than 0.89 mmol/g, by a well described general procedure (cf. Bunin, B. A. The Combinatorial Index, Academic Press, 1998, p. 62-63; Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett. 1996, 37, 937-940; Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589-1592; Cao, J.; Cuny, G. D.; Hauske, J. R. Molecular Diversity 1998, 3, 173-179): N-methylmorpholine or pyridine as base and 4-nitrophenylchloroformate are successively added to a Wang resin pre-swollen in dichloromethane (DCM) or tetrahydrofuran (THF) at ambient temperature. The mixture is stirred overnight. The resin is then washed successively with THF, diethyl ether and DCM then dried overnight under reduced pressure at 50xc2x0 C.
Method A
Preparation of Monoprotected Symmetrical Diamines 
General procedure: as already described in the literature (Dixit, D. M.; Leznoff, C. C. J. C. S. Chem. Comm. 1977, 798-799; Dixit, D. M.; Leznoff, C. C. Israel J. Chem. 1978, 17, 248-252; Kaljuste K.; Unden, A. Tetrahedron Lett. 1995, 36, 9211-9214; Munson, M. C.; Cook, A. W.; Josey, J. A.; Rao, C. Tetrahedron Lett. 1998, 39, 7223-7226), a p-nitrophenylcarbonate Wang resin is treated with a large excess of symmetrical diamine (10-20 equivalents), in an aprotic solvent such as DCM or DMF, in order to produce a monoprotected diamine resin after stirring overnight.
Preparation of Thiourea Resins 
General procedure: aromatic and heteroaromatic isothiocyanates (5-10 equivalents) are added (Smith, J.; Liras, J. L.; Schneider, S. E.; Anslyn, E. V. J. Org. Chem. 1996, 61, 8811-8818) to monoprotected symmetrical diamines in a solvent such as DCM or DMF stirred overnight at ambient temperature. Washed successively with DMF and DCM, the thiourea resin is isolated then dried overnight under reduced pressure at 50xc2x0 C.
(phenylaminothioyl)ethyl Carbamate Wang Resin 
Phenylisothiocyanate (1 ml; 8.5 mmol; 5 eq.) is added to an ethylene diamine N-carbamate Wang resin (2 g; 1.72 mmol; 0.86 mmol/g) swollen in DCM (50 ml). After stirring overnight at ambient temperature, the resin is washed successively with DMF (5xc3x9720 ml) and DCM (5xc3x9720 ml). The success of the coupling is monitored using the Kaiser ninhydrin test (Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I. Anal. Biochem. 1970, 34, 595-598). A pale yellow resin (1.79 g) is obtained with a load of 0.648 mmol/g calculated from the elemental analysis of sulphur.
Synthesis of 2-arylimino-2,3-dihydrothiazoles 
General procedure: regioselective cyclization stage (Korohoda, M. J.; Bojarska, A. B. Polish J. Chem. 1984, 58, 447-453; Ragab, F. A.; Hussein, M. M.; Hanna, M. M.; Hassan, G. S.; Kenawy, S. A. Egypt. J. Pharm. Sci. 1993, 34, 387-400; Hassan, H. Y.; El-Koussi, N. A.; Farghaly, Z. S. Chem. Pharm. Bull. 1998, 46, 863-866) takes place in aprotic solvents such as dioxane or DMF at 80xc2x0 C. for 2-3 hours between the thiourea resin and the xcex1-bromoketone (2-5 equivalents). The resin is then washed successively with DMF, methanol and DCM then dried under reduced pressure. The 2-arylimino-2,3-dihydrothiazole resin is cleaved under acid conditions (DCM/trifluoroacetic acid at 50%) for 1-2 hours then rinsed with DCM. The solvent is evaporated off and the free base is isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate), extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
(C17H16ClN3S, MM=329.86): 
2-bromo-4xe2x80x2-chloroacetophenone (30.2 mg; 129 xcexcmol; 2 eq.) dissolved in DMF (1 ml) is added to a thiourea resin prepared above (100 mg; 64.8 xcexcmol; load of 0.648 mmol/g). The mixture is stirred for 2 hours at 80xc2x0 C. The resin is then successively washed with DMF (3xc3x972 ml), methanol (3xc3x972 ml) and DCM (3xc3x972 ml). The release stage, carried out in 1 ml of mixture of DCM/trifluoroacetic acid at 50%, produces an oil after one hour 30 minutes of stirring which is eluted with methanol in a basic alumina cartridge (500 mg, Interchim). The free base is isolated in a quantitative fashion (21.3 mg) in the form of a yellow oil having a purity measured by UV spectrophotometry of 98% at 220 nm.
NMR 1H (DMSO D6, 100 MHz) xcex4: 7.55 (s, 5H); 7.3 (d, 2H, J=7.1 Hz); 6.99 (d, 2H, J=7.1 Hz); 6.21 (s, 1H, H azole); 3.74 (t, 2H, J=6.2 Hz, NCH2); 3.32 (broad s, 2H, NH2); 2.72 (t, 2H, J=6.2 Hz, NCH2). SM/LC: m/z=330 (M+H)+.
A series of 2-arylimino-2,3-dihydrothiazoles was synthesized according to method A using our robotic system (ACT MOS 496):
R1 groups: 
R2 groups: 
R4 represents H, alkyl, carbocyclic or heterocyclic aralkyl optionally situated on the aryl radical;
or then the 
xe2x80x83radical represents a radical of general formula 
xe2x80x83in which i represents an integer from 1 to 3;
it being understood that for R4, when the aryl group is substituted, it can be 1 to 5 times (other than the bond which links it to the remainder of the molecule) by radicals chosen independently from the group composed of a halogen atom and an alkyl or alkoxy radical.
Method B
Preparation of carbamate Wang resins from aminoalkylanilines 
General procedure: as already described (Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227-7230), a p-nitrophenylcarbonate Wang resin is treated with an excess of aminoalkylaniline (5-10 eq.) in DCM or DMF and stirred at ambient temperature overnight. The resin is washed successively with DMF, methanol and DCM then dried overnight under reduced pressure at 50xc2x0 C.
4-aminophenylethyl Carbamate Wang Resin 
A solution of 2-(4-aminophenyl)ethylamine (2.48 g; 17.3 mmol; 5 eq.) in 30 ml of anhydrous DMF is added to a p-nitrophenylcarbonate Wang resin (4.05 g; 3.47 mmol; load of 0.857 mmol/g) pre-swollen in 50 ml of anhydrous DMF. The mixture is stirred at ambient temperature overnight and filtered. The resin is washed successively with DMF (10xc3x9730 ml), methanol (5xc3x9730 ml) and DCM (5xc3x9730 ml). 3.7 g of yellow resin (load of 0.8 mmol/g calculated from the elemental analysis of the nitrogen), giving a positive Kaiser ninhydrin test, is isolated after drying overnight under reduced pressure at 50xc2x0 C.
Preparation of Thiourea Resins with Aliphatic Isothiocyanates 
General procedure: aliphatic isothiocyanates (5-10 equivalents) are added to an aminoalkylaniline resin in a solvent such as DCM or DMF and stirring is carried out overnight at ambient temperature. After washing successively with DMF and DCM, the thiourea resin is isolated and dried overnight under reduced pressure at 50xc2x0 C.
4-{[(phenylethylamino)carbothioyl]amino}-phenylethyl Carbamate Wang Resin 
10 ml of anhydrous DMF and phenylethylisothiocyanate (624 xcexcl, 4 mmol, 10 eq.) are added under an argon atmosphere to the resin described previously (0.5 g; 0.4 mmol; load of 0.8 mmol/g). The reaction medium is stirred overnight at ambient temperature and produces a negative Kaiser ninhydrin test. The resin is then washed successively with DMF (5xc3x9720 ml) and DCM (5xc3x9720 ml). Drying under reduced pressure at 50xc2x0 C. produces 488 mg of resin with a load of 0.629 mmol/g calculated from elemental analysis of the sulphur.
Synthesis of 2-arylimino-2,3-dihydrothiazoles 
General procedure: the cyclization stage takes place in aprotic solvents such as dioxane or DMF at 80xc2x0 C. for 2 hours between the thiourea resin and the xcex1-bromoketone (2-5 equivalents). The resin is then washed successively with DMF, methanol and DCM then dried under reduced pressure. The iminothiazole resin is cleaved by treatment under acid conditions (DCM/trifluoroacetic acid at 50%) for 1-2 hours then rinsed with DCM. The solvent is evaporated off and the free base isolated after extraction under basic conditions (saturated solution of sodium hydrogen carbonate), extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
(C25H24ClN3S, MM=434.01): 
100 mg (62.9 xcexcmol, load of 0.629 mmol/g) of thiourea resin and 2-bromo-4xe2x80x2-chloroacetophenone (30 mg; 125.8 xcexcmol; 2 eq.) are dissolved in 1 ml of DMF and heated to 80xc2x0 C. for 2 hours. The resin is then washed successively with DMF (5xc3x971 ml), methanol (5xc3x971 ml) and DCM (5xc3x971 ml). The resin is stirred in 1 ml of a DCM/trifluoroacetic acid mixture at 50% for one hour and 30 minutes at ambient temperature. The resin is rinsed with DCM (5xc3x971 ml) and the filtrate evaporated under reduced pressure. The residue, dissolved in methanol, is eluted in a basic alumina cartridge (500 mg, Interchim) in order to quantitatively produce (27.3 mg) the expected product in the form of a solid (UV purity: 97%).
NMR 1H (DMSO D6, 100 MHz) xcex4: 7.9 (broad s, 2H, NH2); 7.53 (d, 2H, J=8.5 Hz); 7.32-7.15 (m, 7H); 7.08-6.9 (m, 4H); 6.37 (s, 1H, H azole); 4.07 (m, 2H, NCH2); 3.03 (m, 2H, NCH2); 2.88 (m, 4H). MS/LC: m/z=435 (M+H)+.
A series of 2-arylimino-2,3-dihydrothiazoles was synthesized according to method B with our robotic system (ACT MOS 496):
R1 groups 
R2 groups 
R3 and R4 groups such as those of method A
Method C
Synthesis of 2-arylimino-1,3-thiazole-4(3H)-carboxamides 
General procedure: a regioselective cyclization stage using xcex1-bromopyruvic acid (2-5 eq.) is carried out starting from the thiourea resin prepared in the method A in aprotic solvents such as dioxane or DMF at 80xc2x0 C. for 2-3 hours. The resin is then washed successively with DMF, methanol and DCM then dried under reduced pressure. The peptide coupling (Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 989, 30, 1927-1930) takes place in DMF at ambient temperature for 1-24 hours with different standard coupling agents (4-5 eq.) such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and aminated compounds (4-5 eq.). The 2-arylimino-1,3-thiazole-4(3H)-carboxamide resin is cleaved by treatment under acid conditions (DCM/trifluoroacetic acid to 50%) for 1-2 hours then rinsed with DCM. The solvent is evaporated off and the free base is isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate), extraction is carried out with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
(C27H27BrN4OS, MM=535.51): 
50 mg (27.5 xcexcmol, load of 0.55 mmol/g) of carboxylic acid resin is activated for 15 minutes with 14.8 mg (0.11 mmol, 4 eq.) of N-hydroxybenzotriazole and 35.3 mg (0.11 mmol, 4 eq.) of TBTU in 800 xcexcl of anhydrous DMF. 20.7 mg (0.11 mmol, 4 eq.) of aminodiphenylmethane dissolved in 200 xcexcl of anhydrous DMF is then added and the resin is filtered after stirring overnight at ambient temperature. A sequential washing with DMF (5xc3x971 ml), methanol (5xc3x971 ml) and DCM (5xc3x971 ml) produces a resin which is treated for one hour and 30 minutes under acid conditions (DCM/trifluoroacetic acid at 50%). The resin is rinsed with DCM (5xc3x971 ml) and the filtrate evaporated under reduced pressure. The residue, taken up in methanol, is eluted in a basic alumina cartridge (500 mg, Interchim) in order to produce a pale yellow solid (8.2 mg; yield of 55.7%; UV purity of 94% at 220 nm).
NMR 1H (DMSO D6, 100 MHz, xcex4): 9.6 (d; 1H; J=8.6 Hz; NH); 7.49 (d; 2H; J=8.6 Hz); 7.35 (s; 10H); 6.92 (s; 1H; H azole); 6.91 (d; 2H; J=8.5 Hz); 6.27 (d; 1H; J=8.5 Hz; NHCH); 4.02 (m; 2H; NCH2); 3.45 (broad m; 2H+2H; NH2 and NCH2); 1.55-1.24 (broad m; 4H). MS/LC: m/z=535 (M+H).
A series of 2-arylimino-1,3-thiazole-4(3H)-carboxamides was synthesized according to method C using our robotic system (ACT MOS 496):
R1 and R2 groups already described in method A;
R3=xe2x80x94COxe2x80x94R5;
R4=H;
R5 groups 
Method D
Synthesis of 2-arylimino-1,3-thiazole-4(3H)-carboxamides 
General procedure: a regioselective cyclization stage using xcex1-bromopyruvic acid (2-5 eq.) is carried out starting from the thiourea resin prepared in method B in aprotic solvents such as dioxane or DMF at 80xc2x0 C. for 2-3 hours. The resin is then successively washed with DMF, methanol and DCM then dried under reduced pressure. The peptide coupling (Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1927-1930) takes place in DMF at ambient temperature for 1-24 hours with different standard coupling agents (4-5 eq.) such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and aminated compounds (4-5 eq.). The 2-arylimino-1,3-thiazole-4(3H)-carboxamide resin is cleaved by treatment under acid conditions (DCM/trifluoroacetic acid at 50%) for 1-2 hours then rinsed with DCM. The solvent is evaporated off and the free base is isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate) followed by an extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
(C27H27ClN4OS, MM=491.05): 
Phenylethylisothiocyanate (310 mg; 1.9 mmol; 10 eq.) in 3 ml of dimethylformamide is added to 200 mg (190 xcexcmol, load of 0.946 mmol/g) of aminated resin (see Preparation 20). Stirring overnight at ambient temperature produces a negative Kaiser ninhydrin test. The resin is then successively washed with DMF (5xc3x973 ml) and DCM (5xc3x973 ml) then dried under vacuum for one hour before adding bromopyruvic acid (63.4 mg; 380 xcexcmol; 2 eq.) diluted beforehand in 3 ml of dimethylformamide. The mixture is stirred for 2.5 hours at 80xc2x0 C. The resin is filtered and washed with DMF (5xc3x973 ml), methanol (3xc3x973 ml) then DCM (5xc3x973 ml). The carboxylic acid resin is preactivated for 1 hour with 244 mg (0.76 mmol; 4 eq.) of TBTU diluted in 2 ml of anhydrous DMF. 110 mg (0.76 mmol; 4 eq.) of 4-chlorobenzylamine dissolved in 1 ml of anhydrous DMF is then added and the resin is filtered after stirring overnight at ambient temperature. Sequential washing with DMF (5xc3x973 ml), methanol (3xc3x973 ml) and DCM (3xc3x973 ml) produces a resin which is treated for one hour and 30 minutes under acid conditions (DCM/trifluoroacetic acid at 50%). The resin is rinsed with DCM (5xc3x971 ml) and the filtrate evaporated under reduced pressure. The residue, taken up in DCM, is neutralized with a saturated solution of sodium hydrogen carbonate in order to produce after evaporation a solid (38.2 mg; yield of 41%; UV purity of % to).
NMR 1H (DMSO D6, 400 MHz, xcex4): 9.1 (m, 1H); 7.39 (d, 2H, J=8.4 Hz); 7.33 (d, 2H, J=8.4 Hz); 7.25 (q, 2H, J=6.8 Hz); 7.19 (q, 1H, J=7.2 Hz); 7.11 (m, 4H); 6.8 (d, 2H, J=8 Hz); 6.75 (s, 1H, H azole); 4.34 (d, 2H, J=6 Hz); 4.27 (t, 2H, J=6.8 Hz); 3.14 (m, 1H); 2.89 (t, 2H, J=6.8 Hz); 2.73 (t, 1H, J=7.2 Hz); 2.62 (m, 2H). MS/LC: m/z=491.24 (M+H)30 .
A series of 2-arylimino-1,3-thiazole-4(3H)-carboxamides was synthesized according to method D using our robotic system (ACT MOS 496):
R1 and R2 groups already described in method B
R3=xe2x80x94COxe2x80x94R5
R4=H
R5 groups already described in method C.
Method E
Preparation of Monoprotected Diamine Resin Functionalized with xcex1-bromopyruvic Acid 
General procedure: the monoprotected symmetrical primary or secondary diamine resin (the preparation of which is already described in method A) is functionalized by peptide coupling with xcex1-bromopyruvic acid (10 eq.), DIC (10 eq.) and HOBt (10 eq.) in a solvent such as DMF at ambient temperature. The resin is washed successively with DMF then with DCM after 2 to 24 hours of stirring before being dried under vacuum. The negative Kaiser ninhydrin test indicates a complete functionalization.
N-carbamate of 2-[(3-bromo-2-oxopropanoyl)amino]ethyl Wang Resin 
HOBt (0.93 g, 6.88 mmol) and xcex1-bromopyruvic acid (1.18 g, 6.88 mmol) are dissolved in 28 ml of DMF (0.5 M). DIC (1.07 ml; 6.88 mmol) is then added by syringe to activate the acid. The mixture is stirred for approximately 15 minutes at ambient temperature before adding it to the N-carbamate of ethylene diamine Wang resin (0.8 g; 0.688 mmol; load rate 0.86 mmol/g). After stirring for 3 hours at ambient temperature, the Kaiser ninhydrin test being negative, the resin is filtered and washed successively with DMF (5xc3x9720 ml) then with DCM (5xc3x9720 ml) before being dried under vacuum. An ochre resin (0.812 g) is obtained with a load rate of 0.525 mmol/g calculated from elemental analysis of the bromine.
Synthesis of 2-arylimino-1,3-thiazole-4(3H)-carboxamides 
General procedure: formation of the thiourea is carried out in a solvent such as DMF or dioxane by mixing an equimolar quantity of primary amine and aromatic or heteroaromatic isothiocyanate. After stirring for 2 to 24 hours at ambient temperature, the thiourea (2 to 5 eq.) is added to the functionalized resin then heated at 80xc2x0 C. for 2 to 4 hours. The 2-arylimino-1,3-thiazole-4(3H)-carboxamide resin is cleaved by treatment under acid conditions (DCM/trifluoroacetic acid at 50%) for 1-2 hours then rinsing with DCM. The solvent is evaporated off and the free base isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate), extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
(C22H26N4O3S, MM=426.54): 
18 xcexcl (105 xcexcmol; 2 eq.) of xcex2-(3,4-dimethoxyphenyl)ethylamine and 12.6 xcexcl (105 xcexcmol; 2 eq.) of phenylisothiocyanate are stirred in 1 ml of DMF for 18 hours. The thiourea is added to 100 mg (52.5 xcexcmol; load rate of 0.525 mmol/g) of resin (Preparation 22) and the mixture heated at 80xc2x0 C. for 3 hours. The resin is then filtered then washed successively with DMF (5xc3x971 ml), methanol (5xc3x971 ml) then DCM (5xc3x971 ml). The resin is dried under vacuum before adding 1 ml of a 50% DCM/TFA mixture. Stirring is carried out for 1.5 hours at ambient temperature, the resin is filtered and rinsed with DCM. The residue recovered after evaporation is then eluted with methanol in a basic alumina cartridge in order to isolate 22.2 mg (quantitative yield; UV purity of 93.4% at 230 nm) of a brown solid corresponding to the free amine.
NMR 1H (DMSO D6, 100 MHz, xcex4): 8.42 (m, 1H, NH); 7.32 (t, 2H, J=7.1 Hz); 7.08-6.63 (m, 6H); 5.76 (s, 1H, H azole); 4.31 (t, 2H, J=6.6 Hz); 3.72 (s, 6H, OCH3); 3.32 (broad s, 2H); 3.17 (mn, 2H); 2.89 (m, 2H); 2.62 (m, 2H). MS/LC: m/z=427.17 (M+H)+.
A series of 2-arylimino-1,3-thiazole-4(3H)-carboxamides was synthesized according to method E using our robotic system (ACT MOS 496):
R1 groups: 
R2 groups already described in method A
R3=xe2x80x94COxe2x80x94R5
R4=H
R5 groups: 
Method F
Preparation of Monoprotected Diamine Resins Functionalized with N-protected Amino Acids (Fmoc) 
General procedure: the peptide coupling of the monoprotected diamine resins with N-Fmoc amino acids (4 to 10 eq.) which are commercially available (Bunin, B. A. The Conmbinatorial Index, Academic Press, 1998, p. 77-82) is carried out in DMF at ambient temperature for 1 to 24 hours with different standard coupling agents (4 to 10 eq.) such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), a DIC/N-hydroxybenzotriazole (HOBt) mixture, benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). The resin is then washed successively with DMF and DCM. The coupling sequence can be repeated (1 to two times) until the Kaiser ninhydrin test is negative.
N-carbamate of 4-[({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}acetyl)amino]butyl Wang Resin 
The Fmoc-Gly-OH acid (2.36 g, 7.94 mmol) is activated with HOBt (1.07 g, 7.94 mmol) and of the DIC (1.25 ml, 7.94 mmol) in 22 ml of DMF for 5 minutes before adding the mixture to butylamine N-carbamate Wang resin (1 g, load rate of 0.794 mmol/g) preswollen in 10 ml of DMF. After stirring for 18 hours at ambient temperature, the resin is washed successively with DMF (5xc3x9720 ml) then with DCM (5xc3x9720 ml ) before being dried under vacuum. 1.27 g of pale yellow resin is thus obtained presenting a negative Kaiser ninhydrin test.
Preparation of the Thiourea Resins 
General procedure: a resin described above is deprotected with a 20% DMF/piperidine mixture. After stirring for one hour at ambient temperature, the resin is filtered and washed successively with DMF then with DCM. The deprotection/washing sequence is repeated a second time and the resin is dried under vacuum. The latter is preswollen in a solvent such as DMF or DCM then an aromatic or heteroaromatic isothiocyanate (5 to 10 eq.) is added. The mixture is stirred for 2 to 24 hours at ambient temperature before the resin is filtered and washed successively with DMF then with DCM. The resin is then dried under vacuum and a negative Kaiser ninhydrin test confirms that the substitution reaction is complete.
4-[({[(1-naphthylamino)carbothioyl]amino}acetyl)amino]butyl N-carbamate Wang Resin 
1.27 g of the above resin (see Preparation 23) is deprotected with 14 ml of DMF/piperidine at 20%. The mixture is stirred for one hour at ambient temperature. The resin is then filtered then washed with DMF (5xc3x9730 ml) then with DCM (5xc3x9730 ml). The deprotection/washing sequence is repeated once before the resin is dried under vacuum. 0.781 g of pale yellow resin was thus obtained with a load rate of 0.758 mmol/g calculated after elemental analysis of the sulphur. 416 mg (2.2 mmol, 10 eq.) of 1-naphthylisothiocyanate diluted in 6 ml of DMF is added to 0.3 g (0.22 mmol) of this thiourea resin. The mixture is stirred for 18 hours at ambient temperature. The resin is filtered then washed successively with DMF (5xc3x9720 ml) then with DCM (5xc3x9720 ml). 310 mg of a pale resin yellow is isolated after drying under vacuum with a load rate of 0.66 mmol/g calculated after elemental analysis of the nitrogen.
Synthesis of 2-arylimino-2,3-dihydrothiazoles 
General procedure: the regioselective cyclization stage is carried out in aprotic solvents such as dioxane, DMF or N-methylpyrrolidinone at 80xc2x0 C. for 2 to 3 hours between the thiourea resin and the xcex1-bromoketone (2 to 5 eq.). The resin is then washed successively with DMF, methanol and DCM then dried under reduced pressure. The 2-arylimino-2,3-dihydrothiazole resin is cleaved under acid conditions (DCM/trifluoroacetic acid at 50%) for 1 to 2 hours then rinsed with DCM. The solvent is evaporated off and the free base isolated after treatment under basic conditions (saturated solution of sodium hydrogen carbonate) followed by an extraction with DCM or elution with methanol in a basic alumina cartridge (500 mg, Interchim).
(C25H25ClN4OS, MM=465.02): 
80 mg (52.8 xcexcmol, load rate of 0.66 mmol/g) of thiourea resin (Preparation 24) and 25.1 mg (105.6 mmol, 2 eq.) of 2-bromo-4xe2x80x2-chloroacetophenone are diluted in 1 ml of DMF. The mixture is heated at 80xc2x0 C. for 2 hours. The resin is filtered then washed with DMF (5xc3x971 ml), methanol (5xc3x971 ml) then DCM (5xc3x971 ml) before being dried under vacuum. 1 ml of a 50% DCM/TFA mixture is added followed by stirring for 1 hour 30 minutes. The resin is filtered and rinsed with DCM. The filtrate is evaporated then rediluted in methanol for elution on basic alumina. 20.6 mg (yield of 84%; UV purity of 94.2% at 220 nm) of yellow solid is thus isolated after evaporation corresponding to the free base.
NMR 1H (DMSO D6, 100 MHz, xcex4): 8.36 (t, 1H, J=4.7 Hz, NH); 8.12 (dd, 1H, J=2.1 and 7.3 Hz); 7.87 (dd, 1H, J=2.7 and 6.3 Hz); 7.63-7.34 (m, 8H); 7.13 (dd, 1H, J=1.61 and 6.7 Hz); 6.33 (s, 1H, H azole); 4.44 (broad s, 2H); 3.14 (m, 2H); 2.7 (m, 2H); 1.5 (m, 4H). MS/LC: m/z=465.21 (M+H)+.
A series of 2-arylimino-2,3-dihydrothiazoles was synthesized according to method F using our robotic system (ACT MOS 496):
R1=xe2x80x94C(R11R12)xe2x80x94COxe2x80x94R10
R2, R3 and R4 groups already described in method A
R10 groups: 
R11=H
R12 groups: 